International Publication Number WO92/11034, published Jul. 9, 1992, discloses a method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is resistant to the antineoplastic agent, by the concurrent administration of the antineoplastic agent and a potentiating agent of the formula: 
wherein the dotted line represents an optional double bond, Xxe2x80x2 is hydrogen or halo, and Yxe2x80x2 is hydrogen, substituted carboxylate or substituted sulfonyl. For example, Yxe2x80x2 can be, amongst others, xe2x80x94COORxe2x80x2 wherein Rxe2x80x2 is C1 to C6 alkyl or substituted alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl or -2, -3, or -4 piperidyl or N-substituted piperidyl. Yxe2x80x2 can also be, amongst others, SO2Rxe2x80x2 wherein Rxe2x80x2 is C1 to C6 alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substituted aralkyl. Examples of such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to transformation. Mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993).
In view of the current interest in inhibitors of famesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
Inhibition of farnesyl protein transferase by tricyclic compounds of this invention has not been reported previously. Thus, this invention provides a method for inhibiting farnesyl protein transferase using tricyclic compounds of this invention which: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a famesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras. Several compounds of this invention have been demonstrated to have anti-tumor activity in animal models.
This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
Compounds useful in the claimed methods are represented by Formula 1.0: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
one of a, b, c and d represents N or NR9 wherein R9 is Oxe2x88x92, xe2x80x94CH3 or xe2x80x94(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2; or
each of a, b, c, and d are independently selected from CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR10 (e.g., xe2x80x94OCH3), xe2x80x94COR10, xe2x80x94SR10 (e.g., xe2x80x94SCH3 and xe2x80x94SCH2C6H5), xe2x80x94S(O)tR11 (wherein t is 0, 1 or 2, e.g., xe2x80x94SOCH3 and xe2x80x94SO2CH3), xe2x80x94SCN, xe2x80x94N(R10)2, xe2x80x94NR10R11, xe2x80x94NO2, xe2x80x94OC(O)R10, xe2x80x94CO2R10, xe2x80x94OCO2R11, xe2x80x94CN, xe2x80x94NHC(O)R10, xe2x80x94NHSO2R10, xe2x80x94CONHR10, xe2x80x94CONHCH2CH2OH, xe2x80x94NR10COOR11, 
xe2x80x83xe2x80x94SR11C(O)OR11 (e.g., xe2x80x94SCH2CO2CH3), xe2x80x94SR11N(R75)2 wherein each R75 is independently selected from H and xe2x80x94C(O)OR11 (e.g., xe2x80x94S(CH2)2NHC(O)O-t-butyl and xe2x80x94S(CH2)2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol-5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR10 or xe2x80x94CO2R10;
R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, R7 and R8 each independently represents H, xe2x80x94CF3, xe2x80x94COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)tR11, xe2x80x94NR10COOR11, xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R11, xe2x80x94CO2R10, OPO3R10 or one of R5, R6, R7 and R8 can be take in combination with R40 as defined below to represent xe2x80x94(CH2)rxe2x80x94 wherein r is 1 to 4 which can be substituted with lower alkyl, lower alkoxy, xe2x80x94CF3 or aryl, or R5 is combined with R6 to represent xe2x95x90O or xe2x95x90S and/or R7 is combined with R8 to represent xe2x95x90O or xe2x95x90S;
R10 represents H, alkyl, aryl, or aralkyl (e.g., benzyl);
R11 represents alkyl or aryl;
X represents N, CH or C, which C may contain an optional double bond (represented by the dotted line) to carbon atom 11;
the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently represent xe2x80x94R10, halo, xe2x80x94OR11, xe2x80x94OCO2R11 or xe2x80x94OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR11)2; H and halo, dihalo, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OC(O)R10, H and xe2x80x94OR10, xe2x95x90O, aryl and H, xe2x95x90NOR10 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94 wherein p is 2, 3 or 4;
R represents R40, R42, R44, or R54, as defined below;
R40 represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or xe2x80x94D wherein xe2x80x94D represents 
xe2x80x83wherein R3 and R4 are as previously defined and W is O, S or NR10 wherein R10 is as defined above; said R40 cycloalkyl, alkenyl and alkynyl groups being optionally substituted with from 1-3 groups selected from halo, xe2x80x94CON(R10)2, aryl, xe2x80x94CO2R10, xe2x80x94OR12, xe2x80x94SR12, xe2x80x94N(R10)2, xe2x80x94N(R10)CO2R11, xe2x80x94COR12, xe2x80x94NO2 or D, wherein xe2x80x94D, R10 and R11 are as defined above and R12 represents R10, xe2x80x94(CH2)mOR10 or xe2x80x94(CH2)qCO2R10 wherein R10 is as previously defined, m is 1 to 4 and q is 0 to 4; said alkenyl and alkynyl R40 groups not containing xe2x80x94OH, xe2x80x94SH or xe2x80x94N(R10)2 on a carbon containing a double or triple bond respectively; or
R40 represents phenyl substituted with a group selected from xe2x80x94SO2NH2, xe2x80x94NHSO2CH3, xe2x80x94SO2NHCH3, xe2x80x94SO2CH3, xe2x80x94SOCH3, xe2x80x94SCH3, or xe2x80x94NHSO2CF3, preferably, said group is located in the para (p-) position of the phenyl ring; or
R40 represents a group selected from 
xe2x80x83wherein R20, R21 and R46 are each independently selected from the group consisting of:
(1) H;
(2) xe2x80x94(CH2)qSC(O)CH3 wherein q is 1 to 3 (e.g., xe2x80x94CH2SC(O)CH3);
(3) xe2x80x94(CH2)qOSO2CH3 wherein q is 1 to 3 (e.g., xe2x80x94CH2OSO2CH3);
(4) xe2x80x94OH;
(5) xe2x80x94CS(CH2)w(substituted phenyl) wherein w is 1 to 3 and the substitutents on said substituted phenyl group are the same substitutents as described below for said substituted phenyl (e.g., xe2x80x94Cxe2x80x94Sxe2x80x94CH2xe2x80x944-methoxyphenyl);
(6) xe2x80x94NH2;
(7) xe2x80x94NHCBZ (wherein CBZ stands for carbonylbenzyloxyxe2x80x94i.e., CBZ represents xe2x80x94C(O)OCH2C6H5);
(8) xe2x80x94NHC(O)OR22 wherein R22 is an alkyl group having from 1 to 5 carbon atoms (e.g., R22 is t-butyl thus forming xe2x80x94NHBOC wherein BOC stands for tert-butyloxycarbonylxe2x80x94i.e., BOC represents xe2x80x94C(O)OC(CH3)3), or R22 represents phenyl substituted with 1 to 3 alkyl groups (e.g., 4-methylphenyl);
(9) alkyl (e.g., ethyl);
(10) xe2x80x94(CH2)kphenyl wherein k is 1 to 6, usually 1 to 4 and preferably 1 (e.g., benzyl);
(11) phenyl;
(12) substituted phenyl (i.e., phenyl substituted with from 1 to 3 substituents, preferably one) wherein the substituents are selected from the group consisting of: halo (e.g., Br, Cl, or I, with Br being preferred); NO2; xe2x80x94OH; xe2x80x94OCH3; xe2x80x94NH2; xe2x80x94NHR22; xe2x80x94N(R22)2; alkyl (e.g., alkyl having from 1 to 3 carbons with methyl being preferred); xe2x80x94O(CH2)tphenyl (wherein t is from 1 to 3 with 1 being preferred); and xe2x80x94O(CH2)tsubstituted phenyl (wherein t is from 1 to 3 with 1 being preferred); examples of substituted phenyls include, but are not limited to, p-bromophenyl, m-nitrophenyl, o-nitrophenyl, m-hydroxy-phenyl, o-hydroxyphenyl, methoxyphenyl, p-methylphenyl, m-methyl-phenyl, and xe2x80x94OCH2C6H5;
(13) naphthyl;
(14) substituted naphthyl, wherein the substituents are as defined for substituted phenyl above;
(15) bridged polycyclic hydrocarbons having from 5 to 10 carbon atoms (e.g., adamantyl and norbornyl);
(16) cycloalkyl having from 5 to 7 carbon atoms (e.g., cyclopentyl, and cyclohexyl);
(17) heteroaryl (e.g., pyridyl, and pyridyl N-oxide);
(18) hydroxyalkyl (e.g., xe2x80x94(CH2)vOH wherein v is 1 to 3, such as, for example, xe2x80x94CH2OH);
(19) substituted pyridyl or substituted pyridyl N-oxide wherein the substituents are selected from methylpyridyl, morpholinyl, imidazolyl, 1-piperidinyl, 1-(4-methylpiperazinyl), xe2x80x94S(O)tR11, or any of the substituents given above for said substituted phenyl, and said substitutents are bound to a ring carbon by replacement of the hydrogen bound to said carbon; 
(23) xe2x80x94NHC(O)xe2x80x94(CH2)kphenyl or xe2x80x94NH(O)xe2x80x94(CH2)k-substituted phenyl, wherein said k is as defined above (i.e., 1-6, usually 1-4 and preferably 1); 
wherein R50 represents H, alkyl (e.g., methyl), alkylcarbonyl (e.g., CH3C(O)xe2x80x94), alkyloxycarbonyl (e.g., xe2x80x94C(O)Oxe2x80x94txe2x80x94C4H9, xe2x80x94C(O)OC2H5, and xe2x80x94C(O)OCH3), haloalkyl (e.g., trifluromethyl), or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl; Ring V includes 
examples of Ring V include: 
(25) xe2x80x94NHC(O)CH2C6H5 or xe2x80x94NHC(O)CH2-substituted-C6H5, for example xe2x80x94NHC(O)CH2-p-hydroxyphenyl, xe2x80x94NHC(O)CH2-m-hydroxyphenyl, and xe2x80x94NHC(O)CH2-o-hydroxyphenyl;
(26) xe2x80x94NHC(O)OC6H5; 
(30) xe2x80x94OC(O)-heteroaryl, for example 
(31) xe2x80x94O-alkyl (e.g., xe2x80x94OCH3);
(32) xe2x80x94CF3;
(33) xe2x80x94CN;
(34) a heterocycloalkyl group of the formula 
(35) a piperidinylgroup of the formula 
xe2x80x83wherein R85 is H, alkyl, or alkyl substituted by xe2x80x94OH or xe2x80x94SCH3; or
R20 and R21 taken together form a xe2x95x90O group and the remaining R46 is as defined above; or
Two of R20, R21 and R46 taken together form piperidine Ring V 
wherein R50 represents H, alkyl (e.g., methyl), alkylcarbonyl (e.g., CH3C(O)xe2x80x94), alkyloxycarbonyl (e.g., xe2x80x94C(O)Oxe2x80x94txe2x80x94C4H9, xe2x80x94C(O)OC2H5, and xe2x80x94C(O)OCH3), haloalkyl (e.g., trifluro-methyl), or xe2x80x94C(O)NH(R10) wherein R10 is H or alkyl; Ring V includes 
examples of Ring V include: 
with the proviso R46, R20, and R21 are selected such that the carbon atom to which they are bound does not contain more than one heteroatom (i.e., R46, R20, and R21 are selected such that the carbon atom to which they are bound contains 0 or 1 heteroatom);
R44 represents 
xe2x80x83wherein R25 represents heteroaryl (e.g., pyridyl or pyridyl N-oxide), N-methylpiperidinyl or aryl (e.g., phenyl and substituted phenyl); and R48 represents H or alkyl (e.g., methyl);
R54 represents an N-oxide heterocyclic group of the formula (i), (ii), (iii) or (iv): 
xe2x80x83wherein R56, R58, and R60 are the same or different and each is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR10, xe2x80x94C(O)R10, xe2x80x94SR10, xe2x80x94S(O)eR11 (wherein e is 1 or 2), xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94CO2R10, xe2x80x94OCO2R11, xe2x80x94OCOR10, alkyl, aryl, alkenyl or alkynyl, which alkyl may be substituted with xe2x80x94OR10, xe2x80x94SR10 or xe2x80x94N(R10)2 and which alkenyl may be substituted with OR11 or SR11; or
R54 represents an N-oxide heterocyclic group of the formula (ia), (iia), (iiia) or (iva): 
xe2x80x83wherein Y represents N+xe2x80x94Oxe2x88x92 and E represents N; or
R54 represents an alkyl group substituted with one of said N-oxide heterocyclic groups (i), (ii), (iii), (iv), (ia), (iia), (iiia) or (iva);
Z represents O or S such that R can be taken in combination with R5, R6, R7 or R8 as defined above, or R represents R40, R42, R44 or R54.
Examples of R20, R21, and R46 for the above formulas include: 
Examples of R25 groups include: 
wherein Y represents N or NO, R28 is selected from the group consisting of: C1 to C4 alkyl, halo, hydroxy, NO2, amino (xe2x80x94NH2), xe2x80x94NHR30, and xe2x80x94N(R30)2 wherein R30 represents C1 to C6 alkyl.
Tricyclic compounds useful in the methods of this invention are described in: (1) U.S. Pat. No. 5,151,423; (2) U.S. Pat. No. 4,826,853; (3) U.S. 5,089,496; (4) WO 88/03138 published on May 5, 1988 (PCT/US87/02777); and (5) U.S. Pat. No. 5,104,876; the disclosures of each being incorporated herein by reference thereto. Those compounds within the scope of this invention which are not described in these documents are described herein.
This invention also provides novel compounds of Formula 1.0 having the formula: 
wherein all substituents are as defined for Formula 1.0
This invention further provides novel compounds of Formula 1.0 having the formula: 
wherein all substituents are as defined for Formula 1.0
Additionally, this invention provides novel compounds of Formula 1.0 having the formula: 
wherein all substituents are as defined for Formula 1.0.
Compounds of Formula 5.2 include compounds wherein the substituents R20, R21, and R46 are selected such that when one of said substituents R20, R21, and R46 (e.g., R46) is selected from the group consisting of: (1) H, (2) xe2x80x94OH, (3) xe2x80x94NH2, (4) xe2x80x94NHC(O)OR22, (5) alkyl, (6) phenyl, (7) heteroaryl, (8) hydroxyalkyl, (9) substituted pyridyl, (10) substituted phenyl and (11) xe2x80x94O-alkyl, then the remaining two of said substituents R20, R21 and R46 (e.g., R20 and R21) cannot both be H when: (a) R1 and R2 are both H, and (b) the double bond between C-5 and C-6 is absent, and (c) both A and B are H2, and (d) R4 is H, and (e) R3 is H or Cl at C-8. Compounds of Formula 5.2 also include compounds wherein when R46 is a group (1) to (11) defined above then R20 and R21 cannot both be H when: R1 and R2 are both H, and both A and B are H or H2. Compounds of Formula 5.2 further include compounds wherein when R46 is a group (1) to (11) defined above then R20 and R21 cannot both be H when R1 and R2 are both H. Compounds of Formula 5.2 also include compounds wherein two of R20, R21 and R46 are not H when R1 and R2 are both H.
This invention further provides novel compounds of Formula 1.0 having the formula: 
wherein all the substituents are as defined for Formula 1.0. Preferably R25 represents heteroaryl.
This invention also provides novel compounds of the formula 7.0 having the formula: 
wherein R, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above for compounds of the formula 1.0, which compounds are useful in the methods claimed herein.
This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma.
It is believed that this invention also provides a method for inhibiting proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogene, (e.g., neu, src, abl, lck, and fyn), may be inhibited by the tricyclic compounds described herein.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. This invention further provides a method of inhibiting ras farnesyl protein transferase, in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described above.
The tricyclic compounds useful in the methods of this invention inhibit the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.
This invention also provides a process for producing 3-nitro substituted compounds. The process comprises reacting one molar equivalent of a compound: 
wherein R1, R2, R3, R4, A, B, a, b, d, and the dotted lines are as defined for Formula 1.0; and R65 represents H or xe2x80x94OR66 wherein R66 represents alkyl (e.g., C1 to C4 alkyl, preferably ethyl); with one molar equivalent of a nitrating reagent, said nitrating reagent being preformed (i.e., prepared first) by mixing, at cold temperature (e.g., at 0xc2x0 C.) equimolar amounts of tetrabutyl ammonium nitrate with TFAA; the reaction of the nitrating reagent with the compound of Formula 1.0 g taking place in a suitable aprotic solvent (e.g., CH2Cl2, CHCl3, toluene or THF); said reaction with said nitrating reagent being conducted at a temperature and for a period of time sufficient to allow the reaction to proceed at a reasonable rate to produce the desired final 3-nitro compound of Formula 1.0h (described below)xe2x80x94i.e., the reaction of the compound of Formula 1.0 g with said nitrating reagent is conducted at an initial temperature of 0xc2x0 C., and said reaction temperature is thereafter allowed to rise to about 25xc2x0 C. during the reaction time period. The reaction usually proceeds overnight to completion, i.e., the reaction usually proceeds for about 16 hours. The reaction can be conducted within a temperature of 0xc2x0 C. to about 25xc2x0 C. during a time period of about 10 to about 24 hours. Preferably the reaction is initially conducted at 0xc2x0 C. and the temperature is allowed to warm up to 25xc2x0 C. The reaction produces the 3-nitro compound (1.0h): 
The compound of Formula 1.0 h can then be converted to other 3-substituted products by methods well known to those skilled in the art. For example, the 3-nitro compounds can be converted to 3-amino, 3-halo, 3-cyano, 3-alkyl, 3-aryl, 3-thio, 3-arylalkyl, 3-hydroxyl, and 3xe2x80x94OR67 wherein R67 is alkyl or aryl. The 3-substituted compounds can then be converted to final products (wherein R65 is R42 or R44) by the procedures described herein.
This invention also provides a process for producing 3-nitro compounds of the formula (1.0i): 
by producing a compound of Formula 1.0 h from 1.0 g as described above; and then hydrolyzing the compound of Formula 1.0 h by dissolving the compound of Formula 1.0 h in a sufficient amount of concentrated acid (e.g., concentrated HCl or aqueous sulfuric acid), and heating the resulting mixture to a temperature sufficient to remove (hydrolyze) the xe2x80x94C(O)R65 substituent, for example, heating to reflux or to a temperature of about 100xc2x0 C. This hydrolysis process is exemplified in Preparative Example 28.
The compound of Formula 1.0 i can then be converted to other 3-substituted compounds as discussed above for the compounds of Formula 1.0h. The compounds of Formula 1.0 i can then be converted to compounds of this invention by the methods described herein.
This invention also provides a process for producing compounds of the formula (1.0 j): 
by reacting one molar equivalent a compound of formula (1.0 k): 
with one molar equivalent of a nitrating reagent, said nitrating reagent being preformed (i.e., prepared first) by mixing, at cold temperature (e.g., at 0xc2x0 C.) equimolar amounts of tetrabutyl ammonium nitrate with TFAA; the reaction of the nitrating reagent with the compound of Formula 1.0 k taking place in a suitable aprotic solvent (e.g., CH2Cl2, CHCl3, toluene or THF); said reaction with said nitrating reagent being conducted at a temperature and for a period of time sufficient to allow the reaction to proceed at a reasonable rate to produce the desired final 3-nitro compound of Formula 1.0 jxe2x80x94i.e., the reaction of the compound of Formula 1.0k with said nitrating reagent is conducted at an initial temperature of 0xc2x0 C., and said reaction temperature is thereafter allowed to rise to about 25xc2x0 C. during the reaction time period. The reaction usually proceeds overnight to completion, i.e., the reaction usually proceeds for about 16 hours. The reaction can be conducted within a temperature of 0xc2x0 C. to about 25xc2x0 C. during a time period of about 10 to about 24 hours. Preferably the reaction is initially conducted at 0xc2x0 C. and the temperature is allowed to warm up to 25xc2x0 C. In Formulas 1.0j and 1.0 k, R1, R2, R3, R4, A, B, a, b, d, and the dotted lines are as defined for Formula 1.0.
The compounds of Formula 1.0 j can be converted to compounds of Formula 1.0 h by methods described below. Also, as discussed above for the compounds of Formula 1.0 h, the compounds of Formula 1.0 j can be converted to other 3-substituted compounds wherein the substituents are those discussed above for Formula 1.0 h.
The compounds of Formula 1.0 j can be converted to compounds of Formula 1.0 m: 
wherein R68 is H or xe2x80x94COORa wherein Ra is a C1 to C3 alkyl group (preferably R68 is H), by reducing a compound of Formula 1.0 j with a suitable reducing agent (such as sodium borohydride) in a suitable solvent (such as EtOH or MeOH) at a suitable temperature to allow the reaction to proceed at a reasonable rate (e.g., 0 to about 25xc2x0 C.); reacting the resulting product (Formula 1.0 j wherein the xe2x95x90O has been reduced to a xe2x80x94OH) with a chlorinating agent (e.g., thionyl chloride) in an suitable organic solvent (e.g., benzene, toluene or pyridine) at a suitable temperature to allow the reaction to proceed at a reasonable rate (e.g., about xe2x88x9220 to about 20xc2x0 C., preferably at xe2x88x9215xc2x0 C., see, for example Preparative Example 7) to produce a compound of Formula 1.0 n: 
and reacting a compound of Formula 1.0n with a compound of the formula: 
wherein R68 is as previously defined, and is preferably H, in a suitable organic solvent (such as THF or toluene) containing a suitable base (such as Et3N or N-methylmorpholine) at a suitable temperature to allow the reaction to proceed at a reasonable rate (e.g., 25 to about 120xc2x0 C.).
Compounds of Formula 1.0 m can be converted to compounds of this invention by the methods disclosed herein. Also, as discussed above for the compounds of Formula 1.0 h, the compounds of Formula 1.0 m can be converted to other 3-substituted compounds wherein the substituents are those discussed above for Formula 1.0 h.
This invention also provides novel compounds (produced in the above described processes as intermediates to the compounds of this invention) having the formulas: 
wherein all substituents are as defined herein.
Preferably, for the intermediate compounds of the processes of this invention, R1 and R2 are H; R3 is halo, most preferably Cl, in the C-8 position; R4 is H; and A and B are H when the double between C-5 and C-6 is present, and A and B are H2 when the bond between C-5 and C-6 is a single bond (most preferably the bond between C-5 and C-6 is a single bond). Those skilled in the art will appreciate that Rings I, II, and/or III can be further substituted, as described herein, to produce the desired compounds of the invention.
Examples of such novel intermediate compounds include: 
As used herein, the following terms are used as defined below unless otherwise indicated:
M+-represents the molecular ion of the molecule in the mass spectrum;
MH+-represents the molecular ion plus hydrogen of the molecule in the mass spectrum;
Bu-represents butyl;
Et-represents ethyl;
Me-represents methyl;
Ph-represents phenyl;
benzotriazol-1-yloxy represents 
xe2x80x831-methyl-tetrazol-5-ylthio represents 
xe2x80x83alkyl-(including the alkyl portions of alkoxy, alkylamino and dialkylamino)-represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably one to six carbon atoms;
alkanediyl-represents a divalent, straight or branched hydrocarbon chain having from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, the two available bonds being from the same or different carbon atoms thereof, e.g., methylene, ethylene, ethylidene, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CHCH3, xe2x80x94CHCH2CH3, etc.
cycloalkyl-represents saturated carbocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;
heterocycloalkyl-represents a saturated, branched or unbranched carbocylic ring containing from 3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3 hetero groups selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR10-(suitable heterocycloalkyl groups including 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, etc.);
alkenyl-represents straight and branched carbon chains having at least one carbon to carbon double bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to 6 carbon atoms;
alkynyl-represents straight and branched carbon chains having a least one carbon to carbon triple bond and containing from 2 to 12 carbon atoms, preferably from 2 to 6 carbon atoms;
aryl (including the aryl portion of aryloxy and aralkyl)-represents carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted (e.g., 1 to 3) with one or more of halo, alkyl, hydroxy, alkoxy, phenoxy, CF3, amino, alkylamino, dialkylamino, xe2x80x94COOR10 or xe2x80x94NO2; and
halo-represents fluoro, chloro, bromo and iodo; and
heteroaryl-represents cyclic groups, optionally substituted with R3 and R4, having at least one heteroatom selected from O, S or N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms, e.g., triazolyl, 2-, 3- or 4-pyridyl or pyridyl N-oxide (optionally substituted with R3 and R4), wherein pyridyl N-oxide can be represented as: 
The following solvents and reagents are referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or ACOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFM); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); ethyl chloroformate (ClCO2Et); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimde hydrochloride (DEC).
Reference to the position of the substituents R1, R2, R3, and R4 is based on the numbered ring structure: 
For example, R1 can be at the C-4 position and R2 can be at the C-2 or 25 C-3 position. Also, for example, R3 can be at the C-8 position and R4 can be at the C-9 position.
Representative structures of Formula 1.0 include but are not limited to: 
Preferably, for the compounds of Formula 1.0 (including 1.0a to 1.0d):
each of a, b, c, and d are C (carbon); or
one of a, b, c and d (most preferably a) represents N or NO, most preferably N, and the remaining a, b, c and d groups represent CR1 or CR2;
each R1 and each R2 is independently selected from H, halo (e.g., Cl, Br and F), xe2x80x94CF3, xe2x80x94OR10 (e.g., hydroxy and alkoxy (e.g., xe2x80x94OCH3)), alkyl (e.g., methyl and t-butyl, said alkyl group being optionally substituted with halo), benzotriazol-1-yloxy, xe2x80x94S(O)tR11 (e.g., xe2x80x94SCH2CH3), xe2x80x94SR11C(O)OR11 (e.g., xe2x80x94SCH2CO2CH3), xe2x80x94SR10 (e.g., R10 represents xe2x80x94CH2C6H5) and 1-methyl-tetrazol-5-ylthio; most preferably R1 and R2 are independently H, halo, xe2x80x94CF3, lower alkyl (e.g., C1 to C4, more preferably methyl) or benzotriazol-1-yloxy; more preferably R1 is Cl or H, and R2 is H, Cl or Br; still more preferably R1 is at the C-4 position, and R2 is at the C-3 position; even more preferably R2 is Br, Cl or I;
R3 and R4 are the same or different and each independently represents H, halo, xe2x80x94CF3, xe2x80x94OR10, xe2x80x94COR10, xe2x80x94SR10, xe2x80x94S(O)tR11 (wherein t is 0, 1 or 2), xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94OC(O)R10, xe2x80x94CO2R10, xe2x80x94OCO2R11, xe2x80x94C(O)NHR10, xe2x80x94CN, xe2x80x94NR10COOR11, alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR10 or xe2x80x94CO2R10; most preferably R3 and R4 independently represent H. halo, xe2x80x94CF3, xe2x80x94OR10 or alkyl (said alkyl group being optionally substituted with halo); more preferably R3 and R4 independently represent H or halo (e.g., Cl, Br, or F); even more preferably R3 is at the C-8 position and R4 is at the C-9 positon; still more preferably R3 is Cl at the C-8 position and R4 is H at the C-9 position;
R5, R6, R7 and R8 each independently represents H, xe2x80x94CF3 or alkyl (said alkyl optionally being substituted with xe2x80x94OR10); most preferably R5, R6, R7 and R8 independently represent H and alkyl, and more preferably H;
when the optional double bond between carbon atoms 5 and 6 is present, A and B independently represent H, xe2x80x94R10 or xe2x80x94OR10, most preferably H, lower alkyl (C1 to C4) and alkyloxy (i.e., R10 represents alkyl), more preferably H and xe2x80x94OH, and still more preferably H; and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR10)2, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OR10 or xe2x95x90O, most preferably H2, xe2x80x94H and xe2x80x94OH, or xe2x95x90O, and more preferably A represents H2 and B represents H2 or xe2x95x90O;
R represents R42 or R44; and
Z represents O or S, and most preferably O.
Compounds of Formula 5.0 include: 
Compounds of Formula 5.1 include: 
Compounds of Formula 5.2 additionally include: 
Compounds of Formula 5.3 include: 
Compounds of formula 5.3A include: 
For the compounds of Formulas 5.0, 5.0a-5.0g, 5.1, 5.1a-5.1g, 5.2, 5.2a-5.2b, 5.3, 5.3a-5.3g, 5.3A, 5.3Aa-5.3Ag, and 5.3B, the definitions of the substituents are as defined for Formula 1.0.
Preferably, for compounds of Formulas 5.0, 5.0a-5.0g, 5.1, 5.1a-5.1g, 5.2, and 5.2a-5.2b, R46 is selected from piperidine Ring V, heteroaryl, phenyl, substituted phenyl, substituted pyridyl or substituted pyridyl N-oxide, and R20 and R21 are independently selected from H or alkyl. Most preferably, R46 is pyridyl, pyridyl N-oxide or piperidine Ring V. More preferably, R46 is pyridyl, pyridyl N-oxide or piperidine Ring V and both R20 and R21 are hydrogen or both R20 and R21 are alkyl (still more preferably methyl).
Even more preferably, R46 is selected from 3-pyridyl, 4-pyridyl, 3-pyridyl N-oxide, 4-pyridyl N-oxide, 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 4-N-acetylpiperidinyl or 3-N-acetylpiperidinyl, and both R20 and R21 are hydrogen or both R20 and R21 are alkyl (still even more preferably methyl). Even still more preferably, R46 is selected from 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, and 4-pyridyl N-oxide, and both R20 and R21 are hydrogen or both R20 and R21 are methyl.
Examples of the R42 groups include: 
Preferably for the compounds of Formulas 5.3, 5.3a-5.3g, 5.3A, 5.3Aa-5.3Ag, and 5.3B, R25 represents phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or 2-, 3- or 4-pyridyl N-oxide, and most preferably 4-pyridyl or 4-pyridyl N-oxide. More prefereably, R48 represents H or methyl and still more preferably H.
Compounds of the formula 7.0c include compounds of the formula: 
wherein R21, R20, R46, R25 and R48 are as defined above for compounds of the formula 1.0.
Compounds of the formula 7.0b include compounds of the formula: 
wherein R21, R20, R46, R25 and R48 are as defined above for compounds of the formula 1.0.
Compounds of the formula 7.0a include compounds of the formula: 
wherein R21, R20, R46, R25 and R48 are as defined above for compounds of the formula 1.0.
Preferably for compounds of the formula 7.0e, 7.0g and 7.0j the group R46 is selected from piperidine ring V, heteroaryl, phenyl, substituted phenyl, substituted pyridyl or substituted pyridyl N-oxide, and R20 and R21 are independently selected from H or alkyl. Most preferably R is pyridyl, pyridyl N-oxide or piperidine ring V. It is also preferred that R20 and R21 are both H or are both alkyl, preferably methyl.
Preferably for compounds of the formula 7.0f, 7.0h and 7.0k, the group R25 is phenyl, 3-pyridyl, 4-pyridyl, 3-pyridyl N-oxide, 4-pyridyl N-oxide or piperidine ring V. More preferably R48 is H or methyl, with H being most preferred.
Preferably for the compounds of formula 7.0a, 7.0b, 7.0c, 7.0e, 7.0f, 7.0g, 7.0h, 7.0j and 7.0k the groups R5, R6, R7 and R8 are H, and R1, R2, R3 and R4 are independently selected from H, halo, xe2x80x94NO2, xe2x80x94N(R10)2, alkyl, alkenyl, alkynyl, xe2x80x94COR10, xe2x80x94CO2R10, xe2x80x94CF3, xe2x80x94OR10, and xe2x80x94CN, wherein R10 is as defined above for compounds of the formula 1.0.
Representative compounds of the invention include: 
Preferred compounds of this invention are selected from the group consisting of compounds of Examples: 1, 2, 3, 4, 5, 6, 19, 42, 43, 44, 45, 46, 47, 48, 49, 75, 76, 78, 82, 83, 84, 85, 89,121, 180, 182, 183, 184, 187 (6.7 and 6.8), 192, 196, 197, 198, 200, 201, 206, 222, 223, 224, 225, 226, 227, 233, 234, 236, 239, 246, 247, 248, 249, 250, 251, 261, 262, 266, 267, 269, 273, 276, 283, 285, 286, 287, 288, 289, 291, 292, 293, 299, 300, 301, 303, 307, 309, 311, 312, 313, 314, 316, 350, 351, 352, 354 and 356.
More preferred compounds of this invention are selected from the group consisting of compounds of Examples: 1, 2, 42, 43, 75, 78, 82, 180, 183, 187 (6.7 and 6.8), 196, 197, 198, 200, 222, 223, 224, 227, 233, 234, 246, 247, 248, 249, 250, 251, 266, 269, 273, 283, 285, 286, 291, 292, 300, 301, 303, 307, 311, 312, 313, 314, 350, 351, 352, 354 and 356.
Even more preferred compounds of this invention are selected from the group consisting of compounds of Examples: 82, 197, 233, 246, 266, 312, 351, 352, 354 and 356.
Also more preferred are the compounds of Examples: 426, 400-G, 400-C, 400-F, 400-E, 425-H, 401, 400-B, 400, 400-L, 425-U, 413, 400-J, 417-B, 438, 411-W, 425-O, 400-D, 400-K, 410-G and 400-H.
Lines drawn into the ring systems indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and diastereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
Certain tricyclic compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic tricyclic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of Formula 1.0 wherein R is xe2x80x94N(R10)2, and compounds of Formulas 5.3, 5.3A and 5.3B can be prepared by reacting compound 405.00 (described below) with an isocyanate (R10-Nxe2x95x90Cxe2x95x90O) in a solvent such as DMF, CH2Cl2 or THF in accordance with methods known in the art.
The following processes may be employed to produce compounds of the inventionxe2x80x94i.e., compounds of Formula 1.0 represented by compounds of Formulas 5.0, 5.1, 5.2 and 5.3. For purposes of describing the processes, the compounds are represented by Formula 400.00: 
wherein R represents R42 or R44, and all other substitutents are as described herein.
A. A compound of Formula 405.00 may be coupled with a compound of the formula RCOOH in the presence of coupling agent such as DEC, N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC) or N,Nxe2x80x2-carbonyldilmidazole (CDI) to produce compounds of Formula 400.00: 
The reaction is usually conducted in an inert solvent such as THF, DMF or CH2Cl2 at a temperature between about 0xc2x0 C. and reflux, preferably at about room temperature. When the coupling agent is DCC or DEC, the reaction is preferably run in the presence of HOBT. Method A is the method of choice for preparing compounds of this invention.
B. A compound of Formula 405.00 may also be reacted with a compound of Formula 410.00 in the presence of base to produce compounds of Formula 400.00:
405.00+RC(O)Lxe2x86x92400.00.
(410.00)
Representative examples of appropriate bases are pyridine and Et3N. L designates a suitable leaving group. For example, a compound of compound 410.00 may be an acyl halide (e.g., L represents halo) or an acyl anhydride, (e.g., L is xe2x80x94Oxe2x80x94C(O)xe2x80x94R). The leaving group may also be alkoxy, in which case the compounds of Formula 400.00 may be produced by refluxing a compound of Formula 405.00 with an excess of a compound of Formula 410.00.
Compounds of Formula 405.00 may be prepared by cleaving the group COORa from the corresponding carbamates 415.00, for example, via acid hydrolysis (e.g., HCl) or base hydrolysis (e.g., KOH): 
wherein Ra is a group which does not prevent the cleavage reaction, e.g., Ra is an optionally substituted alkyl such as ethyl.
Alternatively, depending upon the nature of Ra, as determined by one skilled in the art, Compound 415.00 may be treated with an orgariometallic reagent (e.g., CH3Li), a reductive reagent (e.g., Zn in acid), etc., to form compounds of Formula 405.00.
Compound 415.00 may be prepared from the N-alkyl compound shown as Formula 420.00 below, in the manner disclosed in U.S. Pat. Nos. 4,282,233 and 4,335,036. 
It also will be apparent to one skilled in the art that there are other methods for converting Compound 420.00 to Compound 405.00. For example, treatment of Compound 420.00 with BrCN via von Braun reaction conditions would provide nitrile 420.00a. Subsequent hydrolysis of the nitrile under either aqueous basic or acidic conditions would produce Compound 405.00. This method is preferable when there is substitution on the piperidine or piperazine ring. 
C. The compounds of Formula 400.00 wherein Z is O or S may be made by an alternative process using direct conversion of the N-alkyl compound 420.00 with an appropriate compound of Formula 410.00 such as an acyl halide or acyl anhydride. Preferably the reaction is run in the presence of an appropriate nucleophile (e.g. LiI, etc.) and solvent (e.g., toluene, dioxane or xylenes). An appropriate base, may be added, and heating may be required. Typically, a temperature ranging from 50-150xc2x0 C. (preferably 100-120xc2x0 C.) is utilized. 
Compound 420.00 is prepared as described in part B above.
Compounds of Formula 400.00, wherein X is carbon and the bond to carbon 11 (C-11) is a single bond, can be prepared by reducing compounds of Formula 405.00, wherein X is carbon and the bond to C-11 is a double bond, with lithium aluminum hydride in THF. Conversion to final products can be done following the process described above for conversion of compounds of Formula 405.00 to compounds of Formula 400.00.
Compounds of Formula 400.00, wherein X is a carbon atom having an exocyclic double bond to carbon 11, may be prepared from compound 420.00 as described above. Compounds of Formula 420.00 may be produced by the methods disclosed generally in U.S. Pat. No. 3,326,924 or alternatively may be prepared by a ring closure reaction, wherein the desired cycloheptene ring is formed by treating compound 425.00 with a super acid. Suitable super acids for this purpose include, for example, HF/BF3, CF3SO3H (triflic acid), CH3SO3H/BF3, etc. The reaction can be performed in the absence of, or with, an inert co-solvent such as CH2Cl2. The temperature and time of the reaction vary with the acid employed. For example, with HF/BF3 as the super acid system the temperature may be controlled so as to minimize side reactions, such as HF addition to the exocyclic double bond. For this purpose, the temperature is generally in the range of from about +5xc2x0 C. to xe2x88x9250xc2x0 C. With CF3SO3H as the super acid system, the reaction may be run at elevated temperatures, e.g., from about 25xc2x0 C. to about 150xc2x0 C. and at lower temperatures but the reaction then takes longer to complete.
Generally the super acid is employed in excess, preferably in amounts of from about 1.5 to about 30 equivalents. 
A ketone compound of Formula 425.00 may be formed by hydrolysis of 430.00, e.g., such as by reacting a Grignard intermediate of Formula 430.00 with an aqueous acid (e.g., aqueous HCl). Ia in Formula 430.00 represents chloro, bromo or iodo. 
The Grignard intermediate 430.00 is formed by the reaction of the cyano compound 435.00 with an appropriate Grignard reagent 440.00 prepared from 1-alkyl-4halopiperidine. The reaction is generally performed in an inert solvent, such as ether, toluene, or THF, under general Grignard conditions e.g., temperature of from about 0xc2x0 C. to about 75xc2x0 C. Alternatively, other organometallic derivatives of the 1alkyl-4-halopiperidine can be employed. 
The cyano compound of Formula 435.00 is produced by converting the tertiary butyl amide of Formula 445.00 with a suitable dehydrating agent, such as POCl3, SOCl2, P2O5, toluene sulfonyl chloride in pyridine, oxalyl chloride in pyridine, etc. This reaction can be performed in the absence of or with a co-solvent, such as xylene.
The dehydrating agent such as POCl3 is employed in equivalent amounts or greater and preferably in amounts of from about 2 to about 15 equivalents. Any suitable temperature and time can be employed for performing the reaction, but generally heat is added to accelerate the reaction. Preferably the reaction is performed at or hear reflux. 
The tert-butylamide of Formula 445.00 may be produced by reaction of a compound of Formula 450.00a and 450.00b, in the presence of base, wherein G is chloro, bromo or iodo. 
The compound of Formula 450.00a may be formed by hydrolysis of the corresponding nitrile wherein the appropriate cyanomethyl pyridine, such as 2-cyano-3-methylpyridine, is reacted with a tertiary butyl compound in acid, such as concentrated sulfuric acid or concentrated sulfuric acid in glacial acetic acid. Suitable tertiary butyl compounds include, but are not limited to, t-butyl alcohol, t-butyl chloride, t-butyl bromide, t-butyl iodide, isobutylene or any other compound which under hydrolytic conditions forms t-butyl carboxamides with cyano compounds. The temperature of the reaction will vary depending upon the reactants, but generally the reaction is conducted in the range of from about 50xc2x0 C. to about 100xc2x0 C. with t-butyl alcohol. The reaction may be performed with inert solvents, but is usually run neat.
An alternative process for the formation of compounds of Formula 400.00a may involve direct cyclization of Compound 455.00 as shown below. 
Cyclization to form the cycloheptene ring may be accomplished with a strong acid (e.g., triflic, polyphosphoric, HF/BF3), and may be performed in an inert solvent, such as ether, toluene or THF. The temperature and time may vary with the acid employed, as described in process A above.
Compounds of Formula 455.00 wherein Zxe2x95x90O or S may be prepared by treating a compound of Formula 425.00 with an appropriate acyl halide or acyl anhydride of formula 410.00. Most preferably this reaction is run in the presence of a good nucleophile, such as LiI, in the appropriate solvent, such as toluene, dioxane or xylene, and at a temperature ranging from 50-150xc2x0 C., preferably 100-120xc2x0 C. 
A second method of preparing compounds of Formula 455.00 involves reacting an unsubstituted piperidylidene compound of Formula 460.00 with the appropriate acyl halide or acyl anhydride of Formula 410.00 in the presence of base, such as pyridine or Et3N. Alternatively, if Lxe2x95x90OH in compound 410.00, then coupling of compound 460.00 with compound 410.00 may require use of a conventional coupling reagent, such as DCC or CDI. 
Compounds of Formula 460.00 may be produced from the corresponding carbamates of Formula 465.00, via acid hydrolysis, using for example, aqueous HCl, or base hydrolysis using for example, KOH. Alternatively, some compounds can be prepared by treating the carbamate, Formula 465.00, with an organometallic reagent, such as methyl lithium or a reductive reagent, such as zinc in acid, etc., depending upon the nature of the Ra group. For example, if Ra is a simple alkyl group, CO2Ra may be cleaved by alkaline hydrolysis at 100xc2x0 C. 
The carbamate compounds of Formula 465.00 may be prepared from the appropriate alkyl compound of Formula 425.00 by treatment with a chloroformate, preferably in an inert solvent, such as toluene, with warming to approximately 80xc2x0 C. Other alternative methods are available for the conversion of 425.00 to 455.00 as previously described (e.g. Von Braun reaction conditions). Compounds of Formula 425.00 may be prepared as described above.
Various methods can be used as described in WO 88/03138 to provide compounds which are substituted on the pyridine ring, i.e., in positions 2-, 3- and or 4-positions of the tricyclic ring system. For example, the cyclization methods described on pages 20-30 of WO 88/03138 can already have the appropriate substituents on the pyridine ring in place. A variety of substituted pyridines are known in the literature and can be employed in these syntheses. Alternatively, the azaketone of Formula XIX (from page 27 of WO 88/03138) 
wherein R1 and R2 are both H can be converted to the appropriately substituted azaketone wherein R1 and R2 are non-H substitutents. If both R1 and R2 are desired to be non-H substitutents the procedure would be repeated.
The azaketone is thus reacted with an oxidizing agent such as meta-chloroperoxybenzoic acid (MCPBA) or hydrogen peroxide to produce the corresponding compound in which the nitrogen of the pyridine ring is as an N-oxide: 
wherein one of axe2x80x2, bxe2x80x2, cxe2x80x2 or dxe2x80x2 is Nxe2x86x92O and the others are CH or CR1 or CR2. This reaction is normally run at temperatures from xe2x88x9215xc2x0 C. to reflux, more typically at about 0xc2x0 C. The reaction is preferably conducted in an inert solvent such as CH2Cl2 for MCPBA or acetic acid for hydrogen peroxide.
The azaketone N-oxide of Formula 470.00a can then be reacted with a chlorinating agent such as SO2Cl2 or SOCl2 to form a compound of Formula 470.00b. Typically, this reaction results in monosubstitution of Cl in the ortho or para-position relative to the N atom of the ring. 
To provide the disubstituted products, steps 1 and 2 above are repeated. 
Typically, the resulting disubstituted compounds have Cl ortho and para relative to the N atom of the pyridine ring.
The mono or disubstituted compounds of Formulas 470.00b and 470.00c above can be reacted with various nucleophiles such as alkoxides, amines, thiols, etc. This will result in compounds where one or both of the Cl substituents are replaced by the nucleophile to provide a compound of Formula 470.00d or a compound easily converted to Formula 470.00d. 
The substituted ketone of Formula 470.00 can then be converted to the desired compound by the methods described above and in WO 88/03138 and in U.S. Pat. No. 3,326,924.
Formula 405.00, wherein R1 or R2 are chlorine, can be made by the following alternate process. 
The N-oxide of Formula 415.00 can be treated with POCl3 to form a compound of Formula 415.01. Typically, this reaction results in mono-substitution of Cl in the ortho or para position relative to the N atom of the ring.
Alternatively, the Cl substituted azaketones of Formula 470.00b or 470.00c above can be converted to the corresponding derivatives of Formula 405.00 above wherein R1 and/or R2 is Cl by methods analogous to those described above. At this point the Cl substituent(s) can be displaced by an appropriate nucleophile to provide the desired substituent. Suitable nucleophiles include alkoxide, amines, thiols, etc. This reaction usually requires higher temperatures (e.g., from about 100xc2x0 to about 200xc2x0 C.) than the displacement reaction to produce ketone 470.00d above. It is also usually conducted in a sealed vessel in an inert solvent. The compound of Formula 405.00 is then converted to a compound of Formula 400.00 as described above.
Various electrophilic species can also be added to the pyridine ring from the corresponding halo-substituted pyridine (Formula 405.00 wherein R1 is halo, preferably bromo or iodo). Transmetallation of the halo derivative using an alkyl lithium (e.g. n-BuLi) provides the lithio derivative, which can then be quenched with the appropriate electrophile (e.g. R1L, etc.).
An alternative process for introducing substituents at the C-3 position of pyridine Ring I of Formula 1.0, involves nitrating a compound of Formula 415.00 (except wherein X is nitrogen) or a compound of Formula 470.00d with tetrbutylammonium nitratexe2x80x94TFAA in CH2Cl2 at a temperature of 0xc2x0 C. to room temperature (about 25xc2x0 C.). The nitro group may then be reduced to the corresponding amine using iron filings in EtOH, or powdered zincxe2x80x94acetic acid in aqueous THF, or powdered Zn and either CuCl2 or CuBr2 in aqueous EtOH. By methods know to those skilled in the art, the amine group can be converted to a variety of substituents, such as, halo, cyano, thio, hydroxyl, alkyl, alkenyl, alkynyl and haloalkyl.
Wherein Z represents sulfur, a compound of Formula 400.00 wherein Z is oxygen is reacted with P2S5, Lawesson""s reagent, or another reagent capable of introducing sulfur in place of oxygen. The reaction may take place at elevated temperature in pyridine, toluene or other suitable solvents. In this and other reactions, numerous conversions of a compound of Formula 400.00 (Z=0) to another compound of Formula 400.00 (Z=S) are possible.
Compounds of formula 400.00 with a double bond between C-5 and C-6 can be prepared by heating a compound of Formula 470.00h in acetic acid with SeO2 to produce a compound of Formula 470.00i. Compounds of Formula 470.00i can be converted to final products according to methods already described. 
Compounds having a piperazine ring bound to the C-11 of the tricyclic nucleus, i.e., Formula 1.0 wherein X is N, are best prepared via alkylation of the appropriately substituted piperazine compound of Formula 700.00 with a compound of Formula 705.00. Compounds of Formula 705.00 contain the appropriately substituted halide (such as Cl, Br, or I) or other similar leaving group (e.g., tosyloxy or mesyloxy). The reaction is usually conducted in an inert solvent, such as THF or toluene, optionally with a base such as Et3N or potassium carbonate, and typically at a temperature range of ambient to reflux to produce a compound of Formula 710.00. 
In this reaction Rg is H, CO2Ra (wherein Ra is a C1 to C4 alkyl group) or C(Z)R. The preparation of compound 705.00 wherein L is Cl is analogous to the procedure described in U.S. Pat. No. 3,409,621. One skilled in the art can prepare other derivatives of 705.00 (e.g., L is Br, I, mesyloxy, or tosyloxy). When Rg is H, C(Z)R or CO2Ra, these are converted to compounds of the invention by processes known in the art.
An alternate route for generating the compound of Formula 710.00 is by reductive amination of the aza ketone 715.00 with the piperazine 700.00. 
The reaction is typically carried out in a polar solvent, such as MeOH or EtOH, optionally in the presence of a dehydrating agent, such as 3 xc3x85 molecular sieves. The intermediate Schiff base can be reduced to the compound of Formula 710.00 by employing a variety of reducing agents, such as NaCNBH3, or catalytic hydrogenation, for example, hydrogen over Pd/C.
When Rg is C(Z)R, these are the compounds of the invention. When Rg is H or CO2Ra, these are converted to compounds of the invention as described herein.
Compounds of Formulas 5.3A and 5.3B, wherein R25 represents a pyridyl N-oxide, can be produced by reacting compounds of Formulas 5.3A and 5.3B, wherein R25 is pyridyl, with a one molar equivalent of an oxidizing agent (such as oxone).
Compounds of Formulas 5.3, 5.3A and 5.3B, wherein R25 represents a pyridyl N-oxide, can be produced by reacting the product of Preparative Example 12 with a peroxyacid (such as MCPBA) to give the corresponding N-oxide intermediate. The desired N-oxide product may be obtained from the N-oxide intermediate by following the procedure of Example 183.
Compounds of the formula 7.0a, 7.0b and 7.0c can be prepared from amines of the formula 7.1a, 7.1b and 7.1c, respectively, by coupling a compound of the formula 7.0a, 7.0b or 7.0c with a carboxylic acid of the formula RCOOH via the method described above for reacting compounds of the formula 405.00. 
Alternatively, a compound of the formula 7.0a, 7.0b or 7.0c is treated with a compound of the formula RC(O)L, where L is a suitable leaving group, via the procedure described above for compounds of the formula 405.00.
Compounds of the formula 7.1a can be prepared from a compound of the formula 420.50, (i.e., a compound of the formula 420.00 wherein A and B are both H, no double bond is present between carbons 5 and 6, or between carbon 11 and X, X is CH, and the N-alkyl group is a methyl group) as shown in Reaction Scheme 1. 
In Step A of Reaction Scheme 1, a compound of the formula 420.50 is reacted with a strong base, such as an lithium diisopropylamide or an alkyllithium reagent (e.g., n-butyllithium), at xe2x88x92100xc2x0 to xe2x88x9210xc2x0 C., preferably at xe2x88x9280xc2x0 to xe2x88x9220xc2x0 C., then treated with methyl iodide to form a compound of formula 7.2a.
In Step B of Reaction Scheme 1, a compound of the formula 7.2a is converted to a compound of the formula 7.3a via substantially the same procedure as described above for formation of compounds of the formula 415.00.
In Step C of Reaction Scheme 1, a compound of the formula 7.3a is hydrolyzed via essentially the same procedure as described above for formation of compounds of formula 405.00, to form a compound of the formula 7.1a.
Compounds of the formula 7.1b can be prepared from a compound of the 420.51 (i.e., a compound of the formula 420.00 wherein A and B are both H, no double bond is present between carbons 5 and 6, a double bond is present between carbon 11 and X, X is C, and the N-alkyl group is a methyl group) via the process shown in Reaction Scheme 2. 
In Step A of Reaction Scheme 2, a compound of the formula 420.51 is reacted with a strong base, such as an lithium diisopropylamide or an alkyllithium reagent (e.g., n-butyllithium), at xe2x88x92100xc2x0 to xe2x88x9210xc2x0 C., preferably at xe2x88x9280xc2x0 to xe2x88x9220xc2x0 C., then treated with a protic solvent, such as an alcohol, preferably MeOH, to form a compound of formula 7.2b.
In Step B of Reaction Scheme 2, a compound of the formula 7.2b is converted to a compound of the formula 7.3b via substantially the same procedure as described above for formation of compounds of the formula 415.00.
In Step C of Reaction Scheme 2, a compound of the formula 7.3b is hydrolyzed via essentially the same procedure as described above for formation of compounds of formula 405.00, to form a compound of the formula 7.1b.
Compounds of the formula 7.1c can be prepared from a compound of the 420.51 via the process shown in Reaction Scheme 3.

In Step A of Reaction Scheme 3, a compound of the formula 420.51 is reacted with a strong base, such as an lithium diisopropylamide or an alkyllithium reagent (e.g., n-butyllithium), at xe2x88x92100xc2x0 to xe2x88x9210xc2x0 C., preferably at xe2x88x9280xc2x0 to xe2x88x9220xc2x0 C., then treated with methyl iodide to form a compound of formula 7.2c.
In Step B of Reaction Scheme 3, a compound of the formula 7.2c is converted to a compound of the formula 7.3c via substantially the same procedure as described above for formation of compounds of the formula 415.00.
In Step C of Reaction Scheme 1, a compound of the formula 7.3c is hydrolyzed via essentially the same procedure as described above for formation of compounds of formula 405.00, to form a compound of the formula 7.1c.
In the above processes, it is sometimes desirable and/or necessary to protect certain R1, R2, R3 and R4 etc., groups during the reactions. Conventional protecting groups are operable as described in Greene, T. W., xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d John Wiley and Sons, New York, 1981. For example, the groups listed in column 1 of Table 1 may be protected as indicated in column 2 of the table:
Other protecting groups well known in the art also may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures.
Compounds useful in this invention are exemplified by the following preparative examples, which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.